Esters, conjugated => ketones

Prior to tlie advent of tripbenylpbospbine-stab dized CuH [6a, b, 11], Tsuda and Saegusa described use of Gve mole percent MeCu/DtBAL in THE/HMPA to effect bydtoaluminaiion of conjugated ketones and esters [26], Hie likely aluminium etiolate intermediate could be quendied witli water ot TMSCl, ot alkylated/acylated widi various electrophiles fsudi as Mel, allyl bromide, etc. Sdieme 5.5). Mote... 

The Michael reaction occurs with a variety of a,/3-unsaturated carbonyl compounds, not just conjugated ketones. Unsaturated aldehydes, esters, thio-esters, nitriles, amides, and nitro compounds can all act as the electrophilic acceptor component in Michael reactions (Table 23.1). Similarly, a variety of different donors can be used, including /3-diketones, /3-keto esters, malonic esters, /3-keto nitriles, and nitro compounds. 

Other nucleophiles add to conjugated systems to give Michael-type products. Aniline derivatives add to conjugated aldehydes in the presence of a catalytic amount of DBU (p. 488). Amines add to conjugated esters in the presence of InCla, La(OTf)3, or YTb(OTf)3 at 3kbar, for example, to give P-amino esters. This reaction can be initiated photochemically. An intramolecular addition of an amine unit to a conjugated ketone in the presence of a palladium catalyst, or... 

Recently, a thiazolium-catalyzed conjugate addition of acylsilanes to unsaturated esters and ketones was reported (Scheme 61).147... 

Conjugated ketones and esters react with allenylsilanes to yield acylcyclopentenes (Eq. 9.60) [63]. These products are formed by initial 1,4-addition to the conjugated double bond to afford a silyl-stabilized vinyl cation intermediate. 1,2-Silyl migration gives rise to a second silyl-stabilized vinyl cation which cyclizes to the acyl cyclopen-tene (Scheme 9.14). 

Conjugated ketones and esters generally react with chloroform under basic conditions by Michael-type addition of the trichloromethyl anion to the C=C bond or by insertion of dichlorocarbene into the C=C bond, depending on the substitution pattern of the conjugated system (see Sections 6.4 and 7.3). The corresponding reaction with bromoform under basic conditions produces 1,1-dibromocyclopropanes. 

Absorption at 240-250 nm by 4//-pyrans has been noted (61CB1784), although this has been disputed and in general 4//-pyrans are characterized by a weak shoulder at ca. 225 nm (69JOC3169). Introduction of an ethoxycarbonyl or acetyl group at C-3 causes a shift of the maximum to 270 and 284 nm, respectively, which are further shifted to 285 and 296 nm by a second of these substituents. These maxima are considerably different from those of 0-alkoxy a,/3-unsaturated esters and ketones indicative of additional conjugation with the second double bond of the pyran. 

This is the time to reveal a potential problem. In this synthesis we want conjugate addition. But we might on another occasion want to make the amide 18 so how do we control whether the nucleophile adds direct to the carbonyl group or by conjugate addition 17 In general the reactivity of the electrophile is crucial. Very electrophilic compounds such as acid chlorides or aldehydes tend to prefer direct addition while less electrophilic compounds such as esters or ketones tend to do conjugate addition. 

Palladium catalysts have high tolerance for several functional groups irrespective of their gem- or fc -sclcctivity [4, 6, 7]. Aldehydes, alcohols, saturated or conjugated ketones, esters, sulfones, malonates and silyl ethers have proved to be compatible. The presence of an additional double bond does not modify the coupling, enabling self-dimerization of non-conjugated enynes as depicted in Scheme 8. 

Oxalic esters (for electronic reasons) and formic esters (because of their low steric hindrance) are reactive esters that can acylate ketone enolates formed with NaOR in equilibrium reactions. Formic esters acylate ketones to provide formyl ketones (for example, see Figure 13.61). It should be noted that under the reaction conditions the conjugate base of the active-methylene formyl ketone is formed. The neutral formyl ketone is regenerated upon acidic workup. 

The Cp2TiCl/H20 combination can also be used for the chemoselective reduction of aromatic ketones. The reaction discriminates between ketones and alkenes, between ketones and esters and, remarkably, between conjugated and non-conjugated ketones [80]. There is strong evidence that this reduction proceeds via ketyl-type radicals, which are finally reduced by H-atom transfer from 42 [81]. Under dry conditions, titanium-promoted ketyl radicals from aromatic ketones can be used for intermolecular and intramolecular cross-coupling of ketones [82], Thus, depending on whether water is added or not, complementary and versatile synthetic procedure protocols are available. 

These compounds are largely eno-lized under normal conditions. So, you might ask, why don t they immediately react with themselves by the aldol reaction There are two aspects to the answer. First, the enols are very stable (see Chapter 21 for a full discussion) and, secondly, the carbonyl groups in the unenolized fraction of the sample are poorly electrophilic ester and ketone groups. The second carbonyl group of the enol is not electrophilic because of conjugation. 

Both simple and fused poly substituted pyran-2-ones can be obtained from the reaction between substituted allenyl esters and ketones activated by an electron-withdrawing group. A base-catalysed nucleophilic conjugate addition affords a homoallylic ester and lactonisation completes the one-pot sequence (Scheme 19) <06S2731>. 

Addition to ot, -acetylenic esters and ketones (3, 108 6, 163-164). The addition of organocopper reagents to conjugated acetylenic carbonyl compounds is usually not stereospeciflc, although cis-addition predominates. Japanese chemists have found that the stereoselectivity in the reaction with alkylcopper reagents is markedly enhanced by use of the complex RCu BRj. Thus the reaction of dimethyl acetylenedicarboxylate with n-butylcopper complexed with tri-n-butylboron (or triethylboron) results in exclusive formation of the cis-adduct. In the absence of a trialkylborane the cis- and adducts are formed in the-ratio 85 15. 

Another frequent use of (1) and its enantiomer is the stereospecific conjugate addition of carbonyl compounds to a,p-unsaturated systems. Most published examples contain chiral imine derivatives of cyclic ketones, which add to a,p-unsaturated esters and ketones in a highly stereoselective manner (eq 13 and eq 14). When the ketone is not symmetrically substituted, reaction usually occurs at the most substituted a-position, including those cases where the ketone is a-substituted by oxygen (eq 15). High stereoselectivity can also be achieved when the Michael acceptor is other than an unsaturated ketone or ester, such as a vinyl sulfone (eq 16). Intramolecular variations of this transformation have also been described (eq 17). ... 

Prior to the advent of triphenylphosphine-stabilized CuH [Ga, b, 13], Tsuda and Saegusa described use of five mole percent MeCu/DIBAL in THF/HMPA to effect hydroalumination of conjugated ketones and esters [26]. The likely aluminium enolate intermediate could be quenched with water or TMSCl, or alkylated/acylated with various electrophiles (such as Mel, alLyl bromide, etc. Scheme 5.5). More... 

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